chr22-30019595-C-T

Variant names:

• chr22-30019595-C-T
• rs747238493
• NM_021090.4:c.1936C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_021090.4(MTMR3):​c.1936C>T​(p.Arg646Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R646H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MTMR3 NM_021090.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

Genes affected

MTMR3 (HGNC:7451): (myotubularin related protein 3) This gene encodes a member of the myotubularin dual specificity protein phosphatase gene family. The encoded protein is structurally similar to myotubularin but in addition contains a FYVE domain and an N-terminal PH-GRAM domain. The protein can self-associate and also form heteromers with another myotubularin related protein. The protein binds to phosphoinositide lipids through the PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. The encoded protein has been observed to have a perinuclear, possibly membrane-bound, distribution in cells, but it has also been found free in the cytoplasm. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HORMAD2-AS1 (HGNC:50729): (HORMAD2 and MTMR3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR3	NM_021090.4	MANE Select	c.1936C>T	p.Arg646Cys	missense	Exon 17 of 20	NP_066576.1	Q13615-1
	MTMR3	NM_153050.3		c.1936C>T	p.Arg646Cys	missense	Exon 17 of 20	NP_694690.1	Q13615-2
	MTMR3	NM_153051.3		c.1936C>T	p.Arg646Cys	missense	Exon 17 of 19	NP_694691.1	Q13615-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR3	ENST00000401950.7	TSL:1 MANE Select	c.1936C>T	p.Arg646Cys	missense	Exon 17 of 20	ENSP00000384651.3	Q13615-1
	MTMR3	ENST00000351488.7	TSL:1	c.1936C>T	p.Arg646Cys	missense	Exon 17 of 19	ENSP00000307271.6	Q13615-3
	MTMR3	ENST00000956491.1		c.2038C>T	p.Arg680Cys	missense	Exon 18 of 21	ENSP00000626550.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249608 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461612 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.60
Sift	Benign	0.083	T
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.23		Loss of loop (P = 0.0203)
MVP		0.92
MPC		0.66
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.12
gMVP		0.42
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747238493; hg19: chr22-30415584; COSMIC: COSV100071399; COSMIC: COSV100071399;